1. Field of the Invention
This invention relates to a method and composition for preventing and/or reversing sensorineural hearing loss (SNHL) or toxin-induced hearing loss. More specifically, this invention relates to the use of agents which augment inner ear antioxidant defenses such as adenosine agonists or up-regulating agents and/or agents which increase inner ear glutathione levels to prevent and/or reverse hearing loss induced by noise or toxin. In addition, this invention covers agents that curtail activated programmed cell death pathways and induce/enhance cell repair mechanisms in the inner ear.
2. Description of the Prior Art
SNHL is a very common problem for service members and civilian government employees. Approximately 450 million dollars is spent annually to compensate service members for hearing loss (1). Despite hearing conservation programs, 20-30% of service members develop compensable hearing loss after 10 years in the service (2). The sense of hearing is critical for combat and operational readiness of soldiers and sailors. Both temporary and permanent hearing threshold impairments decrease the ability to communicate and to detect enemy movements (3). Successful implementation of medical treatment to prevent or reverse SNHL as an augmentation to established hearing conservation programs has the potential to save millions of dollars annually and to significantly improve operational readiness.
It is established by the Center for Disease Control that approximately 30 million people in the U.S suffer from SNHL (4). The potential for commercialization is very extensive and would include workers in factories, construction operations, communications, and the airline industry to name a few. Many people working in an environment with damaging noise or toxins would potentially benefit from this treatment. In addition, individuals receiving toxic medications for other forms of therapy (i.e. cancer chemotherapy) can suffer SNHL. An idiopathic form of SNHL also exists.
Currently there are no published effective topical medications to prevent or reverse SNHL. There are no published reports of topical, oral, or systemic medications to treat noise-induced hearing loss (NIHL). This invention differs from mechanical noise attenuators or hearing protection devices in that it does not need to be worn and does not decrease hearing acuity as hearing protectors do. Also, this treatment has the potential to reverse SNHL after it is occurred.
Additionally, cisplatin and aminoglycoside antibiotics such as gentamicin represent useful commonly prescribed therapeutic agents which are toxic to the ear and cause sensorineural hearing loss (6,7,15). Gentamicin is used as an agent delivered indirectly to the inner ear via the middle crossing the round window membrane to destroy balance function in an inner ear affected by Meniere""s disease (28). One of the limitations of this therapy is that the auditory portion of the inner ear is also often damaged leading to sensorineural hearing loss (29). Thus there is a need to selectively protect the auditory hair cells while eliminating inner ear balance function with the gentamicin.
Accordingly, an object of this invention is to prevent sensorineural hearing loss and sensorineural hearing loss caused by noise.
A further object of this invention is to reverse sensorineural hearing loss and sensorineural hearing loss induced by noise.
Yet another object of the invention is to prevent and or reverse hearing loss by the topical application of a compound or combination of compounds which increase inner ear glutathione (GSH) levels and/or augment other inner ear antioxidant defenses, and agents that curtail activated programmed cell death pathways and/or induce/enhance cell repair mechanisms in the inner ear.
Another object of the invention is to protect auditory hair cells from toxic injury by cisplatin or gentamicin.
These and additional objects of the invention are accomplished by preventing and/or reversing inner ear damage due to noise or toxins by upregulating antioxidant enzyme activity by applying agents such as R-N6 Phenylisopropyl adenosine (R-PIA) to the round window membrane of the inner ear or systemically, and/or by also applying agents such as 1-2-oxothiazolidine-4-carboxylic acid (Procysteine) to the round window membrane or by giving it systemically. Selective auditory hair cell protection in the face of gentamicin exposure by concomitant delivery of an NMDA antagonist or glial dervied neurotrophic factor (GDNF) with the gentamicin. These and additional agents are also accomplished by curtailing activated programmed cell death pathways and/or inducing/enhancing cell repair mechanisms in the inner ear. One particularly interesting combination of agents is a mixture of L-N-acetylcysteine (L-NAC) and an ester or salt of salicylic acid. Both agents may be administered orally, which is a desirable characteristic. Low dose salicylate is known to scavenge hydroxyl free radicals (Ohiemiller, In vivo measurement of cochlear reactive oxygen species (ROS) in mice: effects of noise exposure and cochi ear ischemia., Twenty-first Midwinter Research Meeting of the Association for Research in Otolaryngology Association for Research in Otolaryngology, St. Petersburg Beach, Fla., pp. 130, abstract 518 (1998)) and in so doing to form the iron chelator dihydroxybenzoate (DHB). Iron chelators can prevent ROS formation by inhibiting the Fenton reaction (Yamasoba et al., Protection from noise-induced coch/ear damage by iron chelators, Twenty-first Midwinter Research Meeting of the Association for Research in Otolaryngology Association for Research in Otolaryngology, St. Petersburg Beach, Fla., pp. 133, abstract 531 (1998)). Salicylate may also inhibit NF-xcexaB, a potential activator of inflammatory or cell death pathways (Kopp and Ghosh, xe2x80x9cInhibition of NE-k B by sodium salicylate and aspirinxe2x80x9d (see comments), Science, 265, 956-959 1994; Yin et al., The anti-inflammatory agents aspirin and salicylate inhibit the activity of IxcexaB kinase-xcex2, Nature, 396, 77-80 (1998)) or induce heat shock proteins which are known to provide a protective effect for the cochlea (Altschuler et al., In Auditory Plasticity and Regeneration, (Eds, Salvi R. J., H. D., Fiorini F., and Colletti V.) Tieman Medical Publications, New York 1996). L-NAC is another potentially effective candidate because it acts as an ROS scavenger as well as a neuroprotective agent, by increasing intracellular GSH. L-NAC is a well-tolerated antidote to ROS-induced liver damage due to acetaminophen overdose (Kopke et al., Am J Otol, 18,559-571 1997). GSH ester applied to the round window membrane of chinchillas substantially prevents noise-induced hair cell loss (Hight et al., Midwinter Meeting of the Association for Research in Otolaryngology, Vol. 22, Abstract 602 St. Petersburg Beach, Fla. (1999)). Also, alpha lipoic acid, D-methionine, and acetyl-L-camitine, administered either alone or in combination with one or more of the other protective agents described herein, either orally, or through an inner ear catheter, can provide a protective and/or restorative effect (after sudden hearing loss has occurred) for the cochlea. Additionally, the combination of these agents with L-NAC should be more effective than either alpha lipoic acid, D-methionine, or acetyl-L-carnitine alone.
The agent(s) may be applied before, during or after the noise trauma or toxin exposure. Currently there is no published effective topical medication to prevent or reverse SNHL, no published effective medication to prevent or reverse NIHL, and no published medical therapy to selectively protect auditory hair cells from gentamicin toxicity. This invention differs from mechanical noise attenuators or hearing protection devices in that it does not need to be worn and does not decrease hearing acuity as hearing protectors do. Also, this treatment has the potential to reverse SNHL or toxic hearing loss after it is occurred.